Chlamydia trachomatis is an obligate intracellular human pathogen with a unique biphasic developmental growth cycle. It's the etiological agent of trachoma, the world's leading cause of preventable blindness and the most common cause of bacterial sexually transmitted disease. C. trachomatis isolates maintain a highly conserved plasmid of approximately 7.5 kb with copy numbers ranging from 4 to 10 copies per cell. Naturally occurring plasmidless clinical isolates are rare, implicating its importance in chlamydial pathogenesis. Understanding the plasmid's role in chlamydial pathogenesis at a molecular level is an important objective for the future control of chlamydial infections.
Plasmid-deficient C. trachomatis strains and the murine pathogen C. muridarum have been studied in both non-human primate and murine infection models. A common theme of these investigations is that in vivo infection with plasmid-deficient organisms are either asymptomatic or exhibit significantly reduced pathology; providing evidence that the plasmid plays an essential role in chlamydial pathogenesis. The molecular basis of plasmid-mediated virulence is poorly understood but is linked to enhanced pro-inflammatory cytokine stimulation by engagement of Toll-like receptors (TLR) in murine models. Notably, in a macaque model of trachoma, ocular infection with plasmid-deficient organisms generates no clinical pathology but induces strong protective immunity against challenge with fully virulent plasmid bearing organisms; findings that support the use of plasmid-deficient organisms as novel live-attenuated chlamydial vaccines.
The chlamydial plasmid encodes both noncoding RNAs and eight ORFs of unknown function. All eight ORFs, designated pgp1-8, have been shown to be expressed in infected cells. Pgp1 was tentatively identified as a helicase based on homology with E. coli DnaB. Pgp3 is secreted into the host cell cytosol and has been implicated as a potential TLR4 agonist. Moreover, the plasmid functions as a transcriptional regulator of uncharacterized chromosomal genes that are virulence factors important to chlamydial pathogenicity.
The understanding of chlamydial pathogenesis at the molecular level has been hindered in the past by the lack of genetic tools. Very recently, chlamydial forward and reverse genetics systems, and chlamydial transformation, have been described. However, there have been no reports using these tools to characterize chlamydial genes of unknown function. Accordingly, there is a need to identify the molecular basis of chlamydial pathogenesis in order to develop novel methods and agents for preventing and treating chlamydia infection.